The Classic Phase II Trial: Primary Objectives

Phase II trials test the ability of the treatment to produce measurable
tumor shrinkage in a small to medium sized group of patients (typically
20-100), all with the same kind of advanced cancer. A Phase II trial is the
first test directed at any measure of efficacy.

The specific statistic measured is the response rate. Patients who
achieve at least a 50% reduction in the total size of their mesaurable tumors
are considered to have responded. If some tumor remains, it is considered to be
a partial response (PR), but if no detectable tumor remains it is called a
complete response (CR). Both CRs and PRs can relapse, but typically CRs last
longer than PRs. Regardless, on the whole some treatments create more lasting
responses than others. The exact criteria for PR and CR can vary with the
trial, and also the type of cancer. For instance blood cancers which don't form
individual measurable tumors have different criteria for PR and CR.

Patients are often quoted response rates for both experimental and standard
treatments without being told what the response duration might be. This is a
positively key question which you should always ask. Short lived responses may
mean little or nothing in terms of long term patient survival, but long term
responses can indicate some patients are getting a major benefit! Response
durations in journal articles are typically reported in months with numbers
like 2, 7, 12+, 32+. The '+' means that the patient has not yet relapsed. Large
numbers with a plus like "32+" represent hope! On the other hand, small numbers
like "3+" merely mean the follow-up time on that patient is short.

The Classic Phase II Trial: Standard Design

One Stage Design: In the simplest Phase II trial, a pre-determined
number patients with the same type of cancer are given the treatment at the
dose determined in the prior Phase I trial, and the response rate is measured.

Two Stage Design: Many Phase II trials conducted in two stages. The
idea is to avoid giving patients a treatment as soon as it can be known that
the treatment is ineffective. In the two stage design, after a pre-determined
number of patients have been treated, the trial is paused, and the response
rate is evaluated. If the response rate is less than a prespecified minimum
goal, it's concluded that the treatment is not worth pursuing and the trial is
ended. Otherwise, the trial is restarted and a pre-determined number of
additional patients are accrued to permit determinination of the response rate
to the desired accuracy. If you are considering a Phase II trial with a two
stage design, it's worth asking if the trial has reached the second stage,
since if it has, it means at least some of the patients are responding, though
the response rate could still be low. A participating doctor might also know
how exactly how many responded in the first stage.

Many, but not all, Phase II studies are multi-center studies, so you may
have choices as to where to get treated.

Phase II Trials: Variations

Randomization in Phase II Trials: While the classic Phase II design
is not randomized, a noticeable minority of real world Phase II trials are
randomized. In some cases, the goal of the trial is to compare response rates
with two different, but usually related, treatments. For example the trial
might compare the response rate with the combination of "Drug X" and "Drug Y"
to the response rate of "Drug X" alone. From the patient point of view, the
strategic considerations in such a trial are basically identical to the
strategic considerations for a Phase III randomized trial (See Steve's Strategic Guide to Phase III Trials for
suggestions on Phase III trial strategy).

A few Phase II trials randomize aspects of the trial which insignificant to
the patient. For instance, one randomized Phase II trial was only randomized
with respect to whether a core biopsy of the tumor was done before or after
treatment. The idea was to let researchers compare pre and post treatment
biopsy specimens, but one wouldn't expect this to have any effect whatsoever on
the effectiveness of the treatment. You need to pay close attention to just
exactly what aspect of the treatment is being randomized in a randomized Phase
II trial to decide how it affects your evaluation of the trial!

Adjuvant Pilot Studies: Some pilot studies of new adjuvant therapies
are classed as Phase II trials. Adjuvant trials are a completely different
beast from Phase II trials for advanced disease (For more on adjuvant trials,
see Steve's Strategic Guide to Adjuvant
Trials).

Phase I/II Trials: Phase I/II trials combine a Phase I and a Phase II
trial of the same treatment into a single protocol. First the Phase I part of
the trial is done, to determine the Maximum Tolerated Dose (MTD). Then, more
patients are treated at the MTD in the Phase II part, which follows immediately
afterwards. The Phase I and Phase II parts are basically ordinary Phase I or
Phase II trials, so you can analyze the trial as either a simple Phase I or
Phase II trial, depending whether they've reached the Phase II part of the
trial or are still in the Phase I part. The only way to find out is to talk to
the investigators.

Key Eligbility Rules for Phase II Trials

The Classic Phase II Trial Requires You Have Advanced Cancer

If there is a treatment which has a significant chance of curing you, for
ethical reasons you'll be required to have tried that treatment first. Most
advanced cancers do not have a satisfactory treatment, so in most cases there
isn't a requirement to have tried standard therapies first. As with Phase I
trials, if the trial is actually a variant on standard treatment you'll
be required to have yet not tried the standard treatment.

Each Phase II Trial is Limited to a Specific Type of Cancer

In order for the results say anything potentially useful about the
effectiveness of the treatment, the response rate must be determined for
specific cancers, so the treatment is tested in a separate Phase II trial for
each cancer in which it might be useful. There can be several Phase II trials
going on at the same time, each for a different cancer. If initial Phase II
trials are successful (or if more funding becomes available), additional Phase
II trials may be initiated in other cancers. This means there may be results
from prior Phase II trials available to consider as evidence. Some individual
Phase II trials do allow any of a group of biologically related cancers, rather
than just one cancer.

Patients in Phase II trials Must have Measurable Disease

Measurable disease means that you have at least one tumor of a minimum size
whose borders can be clearly visualized on x-rays and whose shrinkage can
therefore be accurately measured. As an example, lung nodules are typically
considered measurable, and pleural effusions are not. You only need one
measurable tumor to have measurable disease: If some of your tumors are
measurable, and others are not, you are still considered to have measurable
disease. Because this matter is technical and changes with improving technology
for visualizing tumors, I strongly suggest asking your doctor whether you have
measurable disease. The exact definition of measurable disease actually varies
with the trial but in most cases a lesion which is clearly measurable would be
accepted as such by most trials.

Phase II Trials: Evidence and Strategies

I believe that Phase II trials can be a particularly good choice if you have
advanced cancer and are looking to get cutting edge treatment. Unlike Phase I
trials, you will get the treatment at what is believed to be the best dose and
schedule, and unlike Phase III trials, being randomized to a treatment you
don't favor is not an issue. As always though, the choice depends on the
particulars.

It's important to realize that most new treatments in clinical trials don't
actually prove to be an advance, so I advise caution when it comes to novel
treatments for which there is little evidence. If there is a known treatment
which offers even a small chance of a cure or meaningful long-term remission,
then unless the evidence for a truly novel treatment in trial is unusually
promising, I recommend you try the known treatment first. Often there won't
actually be a treatment good enough to justify trying before entering a
clinical trial of a truly novel treatment, but it's important that you find
out! If the standard treatment can already produce long term benefit for some
patients, and there isn't anything which looks like a breakthrough in trials, a
Phase II trial which attempts to improve the standard by adding another drug
could be a reasonable option for first line treatment. If you've tried standard
treatments to no avail, or if standard treatments are really not worthwhile,
then, of course, you don't need as much evidence to make a Phase II trial the
best choice.

The key to evaluating the promise of a Phase II trial is in the prior
results. The most applicable and useful data are data from using the treatment
against your kind of cancer. The amount of prior data available will be highly
variable, ranging from brand new treatments just out of Phase I which have only
been tested on a few patients, to situations where hundreds of patients have
been treated with similar or even the same treatment with good result.

Phase I Evidence for Phase II Trials

The Phase I trial for the same treatment may have been published or
presented at a meeting, and the doctors involved with the Phase II trial should
certainly know the results of the prior Phase I. The data from the Phase I
trial will definitely give you a good idea of what the side effects are likely
to be. Data on efficacy from a prior Phase I trial is usually sketchy because
few patients will have been treated at the Maximum Tolerated Dose (which is
usually the most effective dose, and the dose chosen for Phase II), because
patients with varying types of cancer may have been treated, and because
patients in Phase I trials may not be evaluable for response due to lack of
measurable disease. Still, most treatments that have gone on to be approved or
used as standard treatment did have responses in at least some of the Phase I
patients (See for example, Daniel Von Hoff and Judith Turner: Response
rates, duration of response, and dose response effects in Phase I studies of
antineoplastics. Investigational New Drugs 9:115-22, 1991). I believe
you should avoid Phase II trials where the only evidence is the prior Phase I
trial and there was no evidence of patient benefit in that trial. If the data
from Phase I is startling, suggesting a breakthrough, that is probably enough
to make the trial an excellent choice.

Prior Phase II Evidence for Phase II Trials

There may be evidence from other Phase II trials. Sometimes a second
Phase II trial is done to repeat promising results before moving on to Phase
III. Such a confirmatory trial would be an especially good bet! Also results
may be in from Phase II trials in other cancers. While these aren't as
applicable, good results in several types of cancer could indicate the
treatment has relatively broad spectrum efficacy. With some highly targeted
rationally designed treatments, there may be a powerful biological rationale to
suppose the treatment will work on tumors with a specific biological
characteristic, regardless of the specific type of cancer. If your tumor has
the appropriate characteristic, and there are good results in other patients
whose tumors have that characteristic, then the trial could be a good bet, even
if this is the first test in your specific cancer. Anti-angiogenic therapies,
which target tumor blood vessels, may also be relatively less sensitive to
tumor type, although the efficacy of such a treatment might depend on the
nature of the relationship between your tumor and its blood supply, which in
turn could again depend on the type of cancer.

Finally, there may be results of trials of closely related treatments. If a
combination is being tested, maybe there are promising results for similar
combinations. If a combination Phase II trial uses just one experimental
drug, maybe the results of that drug alone are promising, and the trial you are
looking at is an attempt to make it even better by adding other drugs to the
treatment.

Phase II evidence will be in terms of response as above. As I mentioned
above, it's very important to ask yourself if responses are holding, or whether
the responding patients are relapsing. Follow-up times may be quite short, so
information on reqponse duration may be quite limited, but if all the patients
have relapsed despite short follow-up, it's obviously a bad sign! If variations
of the treatment have been in test for a relatively long time there may be
longer follow-up.